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Regulation of cardiomyocyte fate plasticity: a key strategy for cardiac regeneration

Signal Transduction and Targeted Therapy 2021年第2期6卷 436-446页

作者： Rui Gong Zuke Jiang Naufal Zagidullin Tianyi Liu Benzhi Cai Department of Pharmacy at the Second Afliated Hospital and Department of Pharmacology(The Key Laboratory of Cardiovascular ResearchMinistry ol Education)at College of PharmacyHarbin Medical University150086 HarbinChina Department of Internal Diseases Bashkir State Medical UniversityUfa 450008Russia College of Pharmacy University of CincinnatiCincinnatiOHUSA

With the high morbidity and mortality rates,cardiovascular diseases have become one of the most concerning diseases *** heart of adult mammals can hardly regenerate naturally after injury because adult cardiomyocytes have already exited the cell cycle,which subseqently triggers cardiac remodeling and heart *** a series of pharmacological treatments and surgical methods have been utilized to improve heart functions,they cannot replenish the massive loss of beating cardiomyocytes after ***,we summarize the latest research progress in cardiac regeneration and heart repair through altering cardiomyocyte fate plasticity,which is emerging as an effective strategy to compensate for the loss of functional cardiomyocytes and improve the impaired heart ***,residual cardiomyocytes in damaged hearts re-enter the cell cycle to acquire the proliferative capacity by the modifications of cell cycle-related genes or regulation of growth-related ***,non-cardiomyocytes such as cardiac fbroblasts,were shown to be reprogrammed into cardiomyocytes and thus favor the repair of damaged ***,pluripotent stem cells have been shown to transform into cardiomyocytes to promote heart healing after myocardial infarction(MI).Furthermore,in vitro and in vivo studies demonstrated that environmental oxygen,energy metabolism,extracellular factors,nerves,non-coding RNAs,*** the key regulatory functions in cardiac *** fndings provide the theoretical basis of targeting cellular fate plasticity to induce cardiomyocyte proliferation or formation,and also provide the clues for stimulating heart repair after injury.

关键词： cardiac metabolism impaired

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Divergent chondro/osteogenic transduction laws of fibrocartilage stem cell drive temporomandibular joint osteoarthritis in growing mice

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International Journal of Oral Science 2023年第3期15卷 462-475页

作者： Ruiye Bi Qianli Li Haohan Li Peng Wang Han Fang Xianni Yang Yiru Wang Yi Hou Binbin Ying Songsong Zhu State Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases&Department of Orthognathic and TMJ Surgery West China Hospital of StomatologySichuan UniversityChengduChina State Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases&West China Hospital of Stomatology Sichuan UniversityChengduChina Department of Stomatology Ningbo First HospitalNingboChina

The anterior disc displacement(ADD)leads to temporomandibular joint osteoarthritis(TMJOA)and mandibular growth retardation in *** investigate the potential functional role of fibrocartilage stem cells(FCSCs)during the process,a surgical ADDTMJOA mouse model was *** 1 week after model generation,ADD mice exhibited aggravated mandibular growth retardation with osteoarthritis(OA)-like joint cartilage degeneration,manifesting with impaired chondrogenic differentiation and loss of subchondral bone *** tracing using Gli1^(-)CreER^(+);Tm^(fl/-)mice and Sox9-CreER^(+);Tm^(fl/-)mice showed that ADD interfered with the chondrogenic capacity of Gli1+FCSCs as well as osteogenic differentiation of Sox9+lineage,mainly in the middle zone of TMJ ***,a surgically induced disc reposition(DR)mouse model was *** inhibited FCSCs capacity was significantly alleviated by DR treatment in ADD *** both the ADD mice and adolescent ADD patients had significantly relieved OA phenotype and improved condylar growth after DR *** conclusion,ADD-TMJOA leads to impaired chondrogenic progenitor capacity and osteogenesis differentiation of FCSCs lineage,resulting in cartilage degeneration and loss of subchondral bone homeostasis,finally causing TMJ growth *** at an early stage could significantly alleviate cartilage degeneration and restore TMJ cartilage growth potential.

关键词： cartilage impaired degeneration

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Brassinosteroids regulate outer ovule integument growth in part via the control of INNER NO OUTER by BRASSINOZOLE‐RESISTANT family transcription factors

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Journal of Integrative Plant Biology 2020年第8期62卷 1093-1111页

作者： Dandan Jia Lian-Ge Chen Guimin Yin Xiaorui Yang Zhihua Gao Yi Guo Yu Sun Wenqiang Tang Ministry of Education Key Laboratory of Molecular and Cellular Biology Hebei Collaboration Innovation Center for Cell SignalingHebei KeyLaboratory of Molecular and Cellular BiologyCollege of Life SciencesHebei Normal UniversityShijiazhuang 050024China College of Bioscience&Bioengineering Hebei University of Science and TechnologyShijiazhuang 050018China

Brassinosteroids(BRs)play important roles in regulating plant reproductive *** signaling or BR biosynthesis null mutants do not produce seeds under natural conditions,but the molecular mechanism underlying this infertility is poorly *** this study,we report that outer integument growth and embryo sac development were impaired in the ovules of the Arabidopsis thaliana BR receptor null mutant *** expression and RNA-seq analyses showed that the expression of INNER NO OUTER(INO),an essential regulator of outer integument growth,was significantly reduced in the bri1-116 *** INO expression due to overexpression or increased transcriptional activity of BRASSINAZOLE-RESISTANT 1(BZR1)in the mutant alleviated the outer integument growth defect in bri1-116 ovules,suggesting that BRs regulate outer integument growth partially via BZR1-mediated transcriptional regulation of ***,INO expression in bzr-h,a null mutant for all BZR1 family genes,was barely detectable;and the outer integument of bzr-h ovules had much more severe growth defects than those of the bri1-116 ***,our findings establish a new role for BRs in regulating ovule development and suggest that BZR1 family transcription factors might regulate outer integument growth through both BRI1-dependent and BRI1-independent pathways.

关键词： impaired outer steroids

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Targeting angiogenesis for fracture nonunion treatment in inflammatory disease

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Bone Research 2021年第3期9卷 336-348页

作者： Cuicui Wang Jun Ying Xiaolei Nie Tianhong Zhou Ding Xiao Gaurav Swarnkar Yousef Abu-Amer Jianjun Guan Jie Shen Department of Orthopaedic Surgery School of MedicineWashington UniversitySt.LouisMOUSA Department of Orthopaedic Surgery the First Affiliated Hospital of Zhejiang Chinese Medical UniversityHangzhouChina Institute of Orthopaedics and Traumatology the First Affiliated Hospital of Zhejiang Chinese Medical UniversityHangzhouChina Department of Mechanical Engineering&Materials Science School of EngineeringWashington UniversitySt.LouisMOUSA Shriners Hospital for Children St.LouisMOUSA

Atrophic fracture nonunion poses a significant clinical problem with limited therapeutic *** this study,we developed a unique nonunion model with high clinical relevance using serum transfer-induced rheumatoid arthritis(RA).Arthritic mice displayed fracture nonunion with the absence of fracture callus,diminished angiogenesis and fibrotic scar tissue formation leading to the failure of biomechanical properties,representing the major manifestations of atrophic nonunion in the ***,we demonstrated that the angiogenesis defect observed in RA mice was due to the downregulation of SPP1 and CXCL12 in chondrocytes,as evidenced by the restoration of angiogenesis upon SPP1 and CXCL12 treatment in *** this regard,we developed a biodegradable scaffold loaded with SPP1 and CXCL12,which displayed a beneficial effect on angiogenesis and fracture repair in mice despite the presence of ***,these findings strongly suggest that the sustained release of SPP1 and CXCL12 represents an effective therapeutic approach to treat impaired angiogenesis and fracture nonunion under inflammatory conditions.

关键词： CXCL12 angiogenesis impaired

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TSPAN32 suppresses chronic myeloid leukemia pathogenesis and progression by stabilizing PTEN

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Signal Transduction and Targeted Therapy 2023年第4期8卷 1814-1827页

作者： Qiang Qiu Yuanyuan Sun Linyu Yang Qingqing Li Yunyu Feng Mengyuan Li Yuexia Yin Li Zheng Ning Li Huandi Qiu Xue Cui Wei He Bochuan Wang Cong Pan Zi Wang Juan Huang Klarke MSample Zhihui Li Yiguo Hu Department of Thyroid Surgery National Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduSichuanChina State Key Laboratory of Biotherapy and Cancer Center West China HospitalSichuan Universityand Collaborative Innovation Center for BiotherapyChengduSichuanChina Department of Oncology Guizhou Provincial People’s HospitalGuiyangGuizhouChina Sichuan Provincial People’s Hospital ChengduSichuanChina Institute of Life Science eBond Pharmaceutical Technology Ltd.ChengduChina Laboratory of thyroid and parathyroid disease Frontiers Science Center for Disease-related Molecular NetworkWest China HospitalSichuan UniversityChengduSichuanChina Department of Thyroid Surgery West China HospitalSichuan UniversityChengduSichuanChina

We report herein that TSPAN32 is a key node factor for Philadelphia (Ph+) leukemia pathogenesis. We found that TSPAN32expression was repressed by BCR-ABL and ectopic TSPAN32 expression upon Imatinib treatment inhibited the proliferation of Ph+cell lines. Tspan32 overexpression significantly prevented BCR-ABL induced leukemia progression in a murine model and impairedleukemia stem cell (LSC) proliferation. LSCs represent an obstacle for chronic myeloid leukemia (CML) elimination, which continuallyreplenish leukemia cells and are associated with disease relapse. Therefore, the identification of essential targets that contribute tothe survival and self-renewal of LSCs is important for novel curative CML. Mechanistically, TSPAN32 was shown to interact withPTEN, increased its protein level and caused a reduction in PI3K-AKT signaling activity. We also found that TSPAN32 was repressedby BCR-ABL via the suppression of an important transcription factor, TAL1. Ectopic expression of TAL1 significantly increasedTSPAN32 mRNA and protein level, which indicated that BCR-ABL repressed TSPAN32 transcription by decreasing TAL1 ***, we identified a new signaling axis composed of “BCR-ABL-TAL1-TSPAN32-PTEN-PI3K-AKT”. Our findings furthercomplement the known mechanisms underlying the transformation potential of BCR-ABL in CML pathogenesis. This new signalingaxis also provides a potential means to target PI3K-AKT for CML treatment.

关键词： pathogenesis impaired inhibited

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The mechanosensitive lncRNA Neat1 promotes osteoblast function through paraspeckle-dependent Smurf1 mRNA retention

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Bone Research 2022年第2期10卷 338-353页

作者： Caizhi Liu Xingcheng Gao Yuheng Li Weijia Sun Youjia Xu Yingjun Tan Ruikai Du Guohui Zhong Dingsheng Zhao Zizhong Liu Xiaoyan Jin Yinlong Zhao Yinbo Wang Xinxin Yuan Junjie Pan Guodong Yuan Youyou Li Wenjuan Xing Guanghan Kan Yanqing Wang Qi Li Xuan Han Jianwei Li Shukuan Ling Yingxian Li State Key Laboratory of Space Medicine Fundamentals and Application China Astronaut Research and Training CenterBeijingChina The Key Laboratory of Aerospace Medicine Ministry of EducationThe Fourth Military Medical UniversityXi’anShaanxiChina The Second Affiliated Hospital of Soochow University SuzhouJiangsuChina College of Life Sciences Hebei Normal UniversityShijiazhuangHebeiChina Medical College of Soochow University SuzhouJiangsuChina Medical School of Southeast University NanjingJiangsuChina

Mechanical stimulation plays an important role in bone remodeling. Exercise-induced mechanical loading enhances bone strength,whereas mechanical unloading leads to bone loss. Increasing evidence has demonstrated that long noncoding RNAs(lnc RNAs) play key roles in diverse biological, physiological and pathological contexts. However, the roles of lnc RNAs in mechanotransduction and their relationships with bone formation remain unknown. In this study, we screened mechanosensing lnc RNAs in osteoblasts and identified Neat1, the most clearly decreased lnc RNA under simulated microgravity. Of note, not only Neat1 expression but also the specific paraspeckle structure formed by Neat1 was sensitive to different mechanical stimulations, which were closely associated with osteoblast function. Paraspeckles exhibited small punctate aggregates under simulated microgravity and elongated prolate or larger irregular structures under mechanical loading. Neat1 knockout mice displayed disrupted bone formation, impaired bone structure and strength, and reduced bone mass. Neat1 deficiency in osteoblasts reduced the response of osteoblasts to mechanical stimulation. In vivo, Neat1 knockout in mice weakened the bone phenotypes in response to mechanical loading and hindlimb unloading stimulation. Mechanistically, paraspeckles promoted nuclear retention of E3 ubiquitin ligase Smurf1 m RNA and downregulation of their translation, thus inhibiting ubiquitination-mediated degradation of the osteoblast master transcription factor Runx2, a Smurf1 target. Our study revealed that Neat1 plays an essential role in osteoblast function under mechanical stimulation, which provides a paradigm for the function of the lnc RNA-assembled structure in response to mechanical stimulation and offers a therapeutic strategy for long-term spaceflight-or bedrest-induced bone loss and age-related osteoporosis.

关键词： stimulation mec impaired

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LncRNA GACAT2 binds with protein PKM1/2 to regulate cell mitochondrial function and cementogenesis in an inflammatory environment

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Bone Research 2022年第3期10卷 494-508页

作者： Xuan Li Bei-Min Tian Dao-Kun Deng Fen Liu Huan Zhou De-Qin Kong Hong-Lei Qu Li-Juan Sun Xiao-Tao He Fa-Ming Chen State Key Laboratory of Military Stomatology&National Clinical Research Center for Oral Diseases&Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture Department of PeriodontologySchool of StomatologyThe Fourth Military Medical UniversityXi’an 710032P.R.China Department of Stomatology Northwest Women’s and Children’s HospitalXi’an 710032P.R.China Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research Department of PeriodontologyCollege of StomatologyXi’an Jiaotong UniversityXi’an 710032P.R.China Department of Toxicology Shaanxi Provincial Key Laboratory of Free Radical Biology and MedicineThe Ministry of Education Key Laboratory of Hazard Assessment and Control in Special Operational EnvironmentSchool of Public HealthFourth Military Medical UniversityXi’an 710032P.R.China

Periodontal ligament stem cells(PDLSCs) are a key cell type for restoring/regenerating lost/damaged periodontal tissues, including alveolar bone, periodontal ligament and root cementum, the latter of which is important for regaining tooth function. However,PDLSCs residing in an inflammatory environment generally exhibit compromised functions, as demonstrated by an impaired ability to differentiate into cementoblasts, which are responsible for regrowing the cementum. This study investigated the role of mitochondrial function and downstream long noncoding RNAs(lnc RNAs) in regulating inflammation-induced changes in the cementogenesis of PDLSCs. We found that the inflammatory cytokine-induced impairment of the cementogenesis of PDLSCs was closely correlated with their mitochondrial function, and lnc RNA microarray analysis and gain/loss-of-function studies identified GACAT2 as a regulator of the cellular events involved in inflammation-mediated mitochondrial function and ***, a comprehensive identification of RNA-binding proteins by mass spectrometry(Ch IRP-MS) and parallel reaction monitoring(PRM) assays revealed that GACAT2 could directly bind to pyruvate kinase M1/2(PKM1/2), a protein correlated with mitochondrial function. Further functional studies demonstrated that GACAT2 overexpression increased the cellular protein expression of PKM1/2, the PKM2 tetramer and phosphorylated PKM2, which led to enhanced pyruvate kinase(PK) activity and increased translocation of PKM2 into mitochondria. We then found that GACAT2 overexpression could reverse the damage to mitochondrial function and cementoblastic differentiation of PDLSCs induced by inflammation and that this effect could be abolished by PKM1/2 knockdown. Our data indicated that by binding to PKM1/2 proteins, the lnc RNA GACAT2 plays a critical role in regulating mitochondrial function and cementogenesis in an inflammatory environment.

关键词： inflammation inflammatory impaired

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Successful clearance of persistent SARS-CoV-2 asymptomatic infection following a single dose of Ad5-nCoV vaccine

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Signal Transduction and Targeted Therapy 2023年第4期8卷 1942-1952页

作者： Shaofu Qiu Zhao Chen Airu Zhu Qiuhui Zeng Hongbo Liu Xiaoqing Liu Feng Ye Yingkang Jin Jie Wu Chaojie Yang Qi Wang Fangli Chen Lan Chen Sai Tian Xinying Du Qingtao Hu Jinling Cheng Canjie Chen Fang Li Jing Sun Yanqun Wang Jingxian Zhao Jincun Zhao Hongbin Song The Chinese PLA Center for Disease Control and Prevention 100071 BeijingChina State Key Laboratory of Respiratory Disease National Clinical Research Centre for Respiratory DiseaseGuangzhou Institute of Respiratory Healththe First Affiliated Hospital of Guangzhou Medical University510182 GuangzhouGuangdongChina Pediatric Pulmonary Department Guangzhou Women and Children’s Medical CenterGuangzhou Medical University510623 GuangzhouGuangdongChina Guangdong Provincial Center for Disease Control and Prevention 510399 GuangzhouGuangdongChina Guangzhou Laboratory Bio-island510320 GuangzhouGuangdongChina Institute of Infectious Disease Guangzhou Eighth People’s Hospital of Guangzhou Medical University510060 GuangzhouGuangdongChina Shanghai Institute for Advanced Immunochemical Studies School of Life Science and TechnologyShanghaiTech University201210 ShanghaiChina National Clinical Research Center for Infectious Disease Shenzhen Third People’s HospitalThe Second Affiliated HospitalSchool of MedicineSouthern University of Science and Technology518112 ShenzhenGuangdongChina

Persistent asymptomatic(PA)SARS-CoV-2 infections have been *** immune responses in these patients are unclear,and the development of effective treatments for these patients is ***,we report a cohort of 23 PA cases carrying viral RNA for up to 191 *** cases displayed low levels of inflammatory and interferon response,weak antibody response,diminished circulating follicular helper T cells(cTfh),and inadequate specific CD4+and CD8+T-cell responses during infection,which is distinct from symptomatic infections and resembling impaired immune *** of a single dose of Ad5-nCoV vaccine to 10 of these PA cases elicited rapid and robust antibody responses as well as coordinated B-cell and cTfh responses,resulting in successful viral ***-induced antibodies were able to neutralize various variants of concern and persisted for over 6 months,indicating long-term ***,our study provides an insight into the immune status of PA infections and highlights vaccination as a potential treatment for prolonged SARS-CoV-2 infections.

关键词： infection impaired asymptomatic

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PGE2/EP4 skeleton interoception activity reduces vertebral endplate porosity and spinal pain with low-dose celecoxib

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Bone Research 2021年第3期9卷 396-409页

作者： Peng Xue Shenyu Wang Xiao Lyu Mei Wan Xialin Li Lei Ma Neil CFord Yukun Li Yun Guan Wenyuan Ding Xu Cao Department of Orthopaedic Surgery The Johns Hopkins University School of MedicineBaltimoreMDUSA Department of Endocrinology The Third Hospital of Hebei Medical UniversityShijiazhuangHebeiP.R.China Key Laboratory of Orthopaedic Biomechanics of Hebei Province ShijiazhuangHebeiP.R.China Department of Spine Surgery The Third Hospital of Hebei Medical UniversityShijiazhuangHebeiP.R.China Department of Anesthesiology and Critical Care Medicine The Johns Hopkins University School of MedicineBaltimoreMDUSA

Skeletal interoception regulates bone homeostasis through the prostaglandin E2(PGE2)concentration in *** endplates undergo ossification and become highly porous during intervertebral disc degeneration and *** found that the PGE2 concentration was elevated in porous endplates to generate spinal ***,treatment with a high-dose cyclooxygenase 2 inhibitor(celecoxib,80 mg·kg−1 per day)decreased the prostaglandin E2 concentration and attenuated spinal pain in mice with lumbar spine ***,this treatment impaired bone formation in porous endplates,and spinal pain recurred after discontinuing the ***,low-dose celecoxib(20 mg·kg−1 per day,which is equivalent to one-quarter of the clinical maximum dosage)induced a latent inhibition of spinal pain at 3 weeks post-treatment,which persisted even after discontinuing ***,when the prostaglandin E2 concentration was maintained at the physiological level with low-dose celecoxib,endplate porosity was reduced significantly,which was associated with decreased sensory nerve innervation and spinal *** findings suggest that low-dose celecoxib may help to maintain skeletal interoception and decrease vertebral endplate porosity,thereby reducing sensory innervation and spinal pain in mice.

关键词： pain dosage impaired

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The Use of High-Throughput Phenotyping for Assessment of Heat Stress-Induced Changes in Arabidopsis

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Plant Phenomics 2020年第1期2卷 196-209页

作者： Ge Gao Mark A.Tester Magdalena M.Julkowska Division of Biological and Environmental Sciences and Engineering(BESE) King Abdullah University of Science and Technology(KAUST)Thuwal 23955-6900Saudi Arabia

The worldwide rise in heatwave frequency poses a threat to plant survival and *** the new marker phenotypes that show reproducible response to heat stress and contribute to heat stress tolerance is becoming a *** this study,we describe a protocol focusing on the daily changes in plant morphology and photosynthetic performance after exposure to heat stress using an automated noninvasive phenotyping *** stress exposure resulted in an acute reduction of the quantum yield of photosystem II and increased leaf *** longer term,the exposure to heat also affected plant growth and *** tracking the recovery period of the WT and mutants impaired in thermotolerance(hsp101),we observed that the difference in maximum quantum yield,quenching,rosette size,and *** examining the correlation across the traits throughout time,we observed that early changes in photochemical quenching corresponded with the rosette size at later stages,which suggests the contribution of quenching to overall heat *** also determined that 6 h of heat stress provides the most informative insight in plant’s responses to heat,as it shows a clear separation between treated and nontreated plants as well as the WT and *** work streamlines future discoveries by providing an experimental protocol,data analysis pipeline,and new phenotypes that could be used as targets in thermotolerance screenings.

关键词： quenching impaired separation

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